Journal
EUROPEAN JOURNAL OF CANCER
Volume 50, Issue 16, Pages 2866-2876Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.ejca.2014.08.011
Keywords
Selective oestrogen receptor modulator (SERM); Resistance; Insulin-like growth factor-1 receptor beta (IGF-1R beta); Non-genomic pathway; Focal adhesion molecules
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Funding
- Department of Defense Breast Program [W81XWH-06-1-0590, SU2C-AACR-DT0409]
- Susan G. Komen for the Cure Foundation [SAC100009]
- GHUCCTS CTSA [UL1RR031975]
- Lombardi Comprehensive Cancer Center Support Grant (CCSG) Core Grant [NIH P30 CA051008]
- Avon Foundation
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Purpose: Oestrogen (E-2)-stimulated growth re-emerges after a c-Src inhibitor blocking E-2-induced apoptosis. A resulting cell line, MCF-7:PF, is selected with features of functional oestrogen receptor (ER) and over-expression of insulin-like growth factor-1 receptor beta (IGF-1R beta). We addressed the question of whether the selective ER modulator (SERM), 4-hydroxytamoxifen (4-OHT) or other SERMs could target ER to prevent E-2-stimulated growth in MCF-7:PF cells. Methods: Protein levels of receptors and signalling pathways were examined by immunoblotting. Expression of mRNA was measured through real-time RT-PCR. Recruitment of ER or nuclear receptor coactivator 3 (SRC3) to the promoter of ER-target gene was detected by chromatin-immunoprecipitation (ChIP). Results: 4-OHT and other SERMs stimulated cell growth in an ER-dependent manner. However, unlike E-2, 4-OHT suppressed classical ER-target genes as does the pure antioestrogen ICI 182,780 (ICI). ChIP assay indicated that 4-OHT did not recruit ER or SRC3 to the promoter of ER-target gene, pS2. Paradoxically, 4-OHT reduced total IGF-1R beta but increased phosphorylation of IGF-1R beta. Mechanistic studies revealed that 4-OHT functioned as an agonist to enhance the non-genomic activity of ER and activate focal adhesion molecules to further increase phosphorylation of IGF-1R beta. Disruption of membrane-associated signalling, IGF-1R and focal adhesion kinase (FAK), completely abolished 4-OHT-stimulated cell growth. Conclusions: This study is the first to recapitulate a cellular model in vitro of acquired tamoxifen resistance developed in athymic mice in vivo. Importantly, it provides a rationale that membrane-associated pathways may be valuable therapeutic targets for tamoxifen resistant patients in clinic. (c) 2014 Elsevier Ltd. All rights reserved.
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